About 15% of couples have reduced fertility and approximately one-half of these are due to male infertility, usually of genetic origin. Common treatments include drug therapy, surgery, testicular sperm extraction (TESE) and magnelaser therapy. Genetic defects are believed to be the most prevalent cause of abnormalities, which result in the loss of specific DNA segments and ultimately leads to loss of vital genes for sperm production.
There are several technologies currently under development that target male infertility, including recombinant human zona pellucida protein (rhZP3) and glycosylated peptides having biological activity of binding to human spermatozoa, a TIAP polypeptide, and use of N-acetyl-L-cysteine to treat and prevent inflammation-based infertility.
Addressing male contraception is a much trickier subject since men produce approximately 100 million sperm every day, compared to women, who typically produce one functional gamete per month. There are numerous ongoing efforts aimed at male contraception. Such research includes attempting to elucidate the underlying molecular mechanism of fertilization.
Successful fertilization in mammals is dependent upon the species-specific recognition, adhesion, and fusion between sperm and egg. Despite their fundamental importance, little is known about the molecular basis underlying these events. Two sperm-egg recognition events in particular have received the most attention: the initial adhesion between the sperm plasma membrane and the egg extracellular coat, or zona pellucida, and the binding between membranes of the acrosome-reacted sperm and the egg plasma membrane (Primakoff and Myles, 2002; Wassarman et al., 2001). In both instances, candidate receptors have been identified, but thus far, none of these receptors appear to be completely responsible for either sperm-egg binding or sperm-egg fusion (Miller et al., 1992; Nishimura et al., 2001; Rankin et al., 1998). In particular, sperm binding to the zona pellucida is thought to involve recognition of specific glycoside residues on the ZP3 glycoprotein (Florman and Wassarman, 1985), which lead to aggregation of the sperm receptor and trigger acrosomal exocytosis. The nature of the sperm binding oligosaccharides on ZP3 remains unclear, as are the sperm proteins that bind ZP3 (Florman and Wassarman, 1985; Johnston et al., 1998; Miller et al., 1992; Nagdas et at., 1994; Nishimura et al., 2001; Primakoff and Myles, 2002; Rankin et al., 1998; Wassarman et al., 2001).
One candidate that has been extensively studied is β1,4-galactosyltransferase I (GaIT I). A wealth of evidence suggests that GaIT I functions as a ZP3 receptor and participates in G protein-dependent acrosomal exocytosis following ZP3-mediated GaIT I aggregation (Gong et al., 1995; Miller et al., 1992). In this regard, ectopic expression of GaIT I on Xenopus oocytes leads to specific ZP3 binding and G protein activation. Site-directed mutagenesis of the GaIT I cytoplasmic domain prevents ZP3-dependent G protein activation (Shi et al., 2001). Furthermore, overexpression of GaIT I on mouse sperm leads to increased ZP3 binding, G protein activation, and accelerated acrosomal exocytosis (Youakim et al., 1994), whereas GaIT I deletion leads to a loss of ZP3 binding and a concomitant loss of zona-induced acrosome reactions (Lu and Shur, 1997). Nevertheless, GaIT I null sperm are still able to adhere to the egg coat and fertilize the egg, albeit at low efficiency, although they no longer bind ZP3 (Lu and Shur, 1997). This indicates that sperm adhesion to the zona pellucida requires receptors in addition to GaIT I and ZP3, consistent with results from others (Rankin et al., 1998, 2003).